Robert A. Weinberg, PhD
Member, Whitehead Institute
Director, Ludwig Center for Molecular Oncology
Daniel K. Ludwig Professor for Cancer Research
Massachusetts Institute of Technology
Uncovering what makes breast cancer cells resistant to immunotherapy and how to reverse this resistance.
Immunotherapy harnesses the power of one’s own immune system to fight cancer. It is one of the most significant recent advances in cancer medicine and has been particularly successful in some cancers including lung and melanoma. Unfortunately, immunotherapy has been relatively ineffective in treating breast cancer. Both melanoma and lung cancer are easily recognizable by the immune system because they produce foreign-looking proteins that signal the immune system to attack the cells. By unleashing the immune system with therapies called checkpoint inhibitors, the body can launch a robust immune response and destroy the tumor. Unlike melanoma or lung cancer cells, breast cancer cells look too similar to normal breast cells and do not alert the immune system to send in cancer-killing immune cells. Dr. Weinberg is examining the evolution of breast cancer cells to uncover innovative strategies to improve response to checkpoint inhibitors.
Dr. Weinberg was the first to describe the process of epithelial-mesenchymal transition (EMT) that allows breast cancer cells to transform from an epithelial (structural) state to a mesenchymal (mobility) state. In this state, breast cancer cells are able to invade tissue and survive chemotherapy—traits that support metastasis. He has also described ways in which breast cancer cells are able to transform into cancer stem cells—the cells that enable drug resistance within the tumor and are critical to the formation of metastases. Thus far, he and his team showed that breast cancer stem cells are resistant to attack by immunotherapy and while comprising only 10 percent of the tumor, they offer cross-protection to other cancer cells in the tumor. Their current studies suggest a role for the molecule adenosine, which can suppress the immune response.
In the upcoming year, Dr. Weinberg will dig deeper into the tumor immune microenvironment and continue to explore mechanisms of cross-protection by cancer stem cells and whether the cross-protection mechanism is widely used by breast cancer subtypes. If so, it could be targeted in combination with immunotherapy, making the immunotherapy more effective.
Dr. Weinberg is a founding member of the Whitehead Institute for Biomedical Research and the Daniel K. Ludwig Professor for Cancer Research at the Massachusetts Institute of Technology (MIT) and the first Director of the Ludwig Cancer Center at MIT. He is an internationally recognized authority on the genetic basis of human cancer. Dr. Weinberg's team isolated the first human cancer-causing gene, the ras oncogene, and the first known tumor suppressor gene, Rb, the retinoblastoma gene.
Research in Dr. Weinberg's laboratory is focused on attempting to elucidate the biochemical and cell-biological mechanisms that enable carcinoma cells in primary tumors to invade and disseminate, resulting in the formation of metastases in distant sites. Much of this work depends on analyses of the cell-biological program termed the epithelial-mesenchymal transition (EMT). In addition to conferring traits such as motility and invasiveness on epithelial carcinoma cells, activation of this program heightens their resistance to chemotherapeutic attack. In recent years, the Weinberg laboratory has also found that activation of a previously latent EMT program places both normal and neoplastic epithelial cells in a position from which they can enter into a stem cell state. In the case of carcinomas, the tumor-initiating powers resulting from this shift indicates the formation of cancer stem cells (CSCs), which are qualified to serve as founders of new metastatic colonies in distant anatomical sites. Dr. Weinberg's research has increasingly focused on the interaction of CSCs with recruited inflammatory cells and on the later steps of the invasion-metastasis cascade that enables disseminated carcinoma cells to extravasate, thereby setting the stage for the formation of micro- and macroscopic metastatic colonies.
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